Pathology Herpes Simplex Virus o Vesiculo-pustular eruption Macule (flat spot), papule (bump), vesicle (fluid-filled papule, less

s than 1cm), pustule (vesicle with pustular fluid), erythema (red), bulla (fluidfilled papule, greater than 1cm) Multinucleated giant cells Stained w/ H&E very dark purple/blue Nuclei undergo ground glass (frosted, etched look) change in late lesion HSV I, HSV II, Varicella-Zoster Synctia (clumping of giant cells) Intranuclear Inclusion Bodies

Cowdry Type A (eosinophillic) Versus ground glass different stages of infection Present in single cells o Vesicle formation Although normally dont biopsy Well above basal layer of skin (basement membrane) No scar in uncomplicated infection due to distance from basement membrane very superficial Exfoliated cells and cellular debris Some contain CPEs o Herpetic Whitlow Finger Enter through small breaks in the skin Very painful/debilitating Similar regression/latency/reactivation pattern o Genital Herpes Same CPEs Type II o Immunocompromised host Deeper lesion, more extensive Scar formation o Herpes Esophagitis Multiple mucosal ulcerations More common in immunologically compromised host Painful Difficult to eradicate Vocabulary o Gross: Macroscopic o Metaplasia: Substitution of one mature cell type for another Transformation zone of uterine cervix: squamous metaplasia in reproductive years Squamous meet columnar o Atrophy: Loss of cell volume / tissue volume

Reduced in size, cell still intact and alive yet have lost substance Tissue size reduced Same number of cells PDH case: atrophic brain

o o

o
Death o

Radiologist playing fast and loose with terminology In reality some brain tissue probably failed to develop or was lost overall brain would look smaller o Ventricles dilate Hypertrophy: Increase in size of tissue due to increase of individual cell size Frequent in heart (cardiac muscle cells cant multiply) Hypertension Individual cardiac muscle cells have gotten bigger to compensate Hyperplasia: Increase in size of tissue due to increase in cell number Endometrium estrogen stimulation; lining increased in size frequently seen at extremes of reproductive life More cells produced Thyroid hormone stimulation causes cellular outpouching due to increased number Apoptosis: Programmed cell death Necrosis: Pathological cell death Caseation: Necrosis, granular mors gaudet succurere vita death rejoices in teaching life Apoptosis Peripheral localization of chromatin Chromatin disruption Organelle clustering Nucleus systematically degraded into pyknotic (densly staining blue/black blob) then fragment (karyo) Flipping to change distribution of phospholipids in inner/outer membranes Phosphatidylserine: eat me label to macs Degredation is systematic (particularly of nuclear DNA) Apoptotic ladders Part of normal development, response to injury (wound healing), attempt to rid body of cells that have undergone viral/neoplastic changes Lack of apoptosis keloid, appendage formation, etc Two major pathways: Intrinsic: Involves mitochondria, release of cytochrome c, interaction with caspases to nuclear/cytoskeletal breakdown Extrinsic: Death Receptor / Death Domain, receptor-ligand interactions; FAS, TNF Cytotoxic T cells Granzyme B Final common pathway involving caspases* o Cleave cysteine and aspartic acid Cell remains packaged, blebs come off membrane remains intact No big inflammatory response although targeted to be eaten Diabetes: endocrine pancreas islets; lymphocytes engaging -cells to induce apoptosis [ascinar cells feed into intercalating ducts] Lipemia retinalis (vessels filled with triacylglycerides) Very tidy death! Necrosis

Messy death, leakage of cellular contents into surrounding tissue Point of no return: irreversible injury difficult to determine in vivo

Nuclear changes are pathologic indicator Injurious Stimuli: Decreased ATP o Lose electrochemical gradient (Na/K/ATPase) o Loss of energy-dependent cellular function Membrane Damage o Mitochondria Cell death: apoptosis o Lysosome Enzymatic digestion of cell o Plasma membrane Loss of cellular contents Rapid or gradual Increased Intracellular Calcium o Protein breakdown, nuclear breakdown, etc Reactive Oxygen Species Irreversible Nuclear changes: decreased basophilia, etc Membrane completely disrupted Mitochondrial crystals, disrupted cristae , electron densities Ischemia: insufficient blood flow, oxygen flow decreases: hypoxia; no more oxygen for ETC (OxPhos stops, ATP decreases, TCA stops run off of anaerobic glycolysis) pH decreases, glycogen depleted, protein synthesis decreases Influx of Ca, water, Na; efflux K o Sodium pulls in more water Abnormal cellular swelling Calcium Responsibilities Influx into cell or efflux from mito/ER o Decreased ATP o Decreased phospholipids o Decreased pumps/gradient maintenance o Ultimately nuclear damage

Infarction: ischemic (coagulative) necrotic tissue death as a result of ischemia Classical example: myocardial Thrombus: blood clot can cut off blood flow Causes increased eosinophilia (loss of cytoplasmic basophilia & glommed denatured proteins) o Influx of calcium/enzymes nucleases activated and degraded ribosomes/mRNA/etc in cytoplasm Cells more condensed on themselves Most have lost nuclei o Further in process: NO NUCLEI, DENSE eosinophilia Overall structure still maintained With time: healing/inflammation occurs Types of Necrosis

Coagulative: Architecture maintained, ghostlike changes Liquefactive: Architecture not maintained, obliterated, frequently bacterial/fungal infections

Brain tissue: liquefactive necrosis normal when injured by ischemia Tissue abnormal, yet not completely obliterated secondary liquefactive changes large fluid, filled hole Gangrene: clinical, not pathological term Results from longstanding ischemia leading to coagulative necrosis absence of adequate blood flow also prevents healing mummified tissue (dry gangrene) o Few nuclei in underlying dermal tissue o Arthrosclerosis, arteriolesclerosis limits blood flow *Diabetes Wet gangrene: coagulative necrosis due to ischemia with superimposed liquefactive necrosis by bacteria (frequently normal flora) o Tissue dies first, then bacteria eat it o Frequently diabetic neuropathy limits pain Gas Gangrene: Clostridial myonecrosis bacterial infection elaborating toxin attacking previously healthy tissue (form of liquefactive necrosis) BETTER term: myonecrosis Excruciating pain rapid progression Muscle has cooked meat appearance and does not bleed/contract Microscopically: necrotic muscle cells and many bacteria; little inflammation Toxin is leuckocidal, interferes with trafficking signals, BV damaged and out of service toxin causes ischemia, hypoxia Causes: S/P trauma S/P surgery especially GI S/P septic abortion Co-existing colorectal cancer (presenting phenomenan) Primarily hydrogen gas (carbon dioxide lesser), methane Toxins destroy PREVIOUSLY HEALTHY TISSUE Directly responsible for the death of the tissue like a predator o Wet gangrene like a scavenger bacteria didnt kill tissue, but fed after ischemic hypoxia Progression: Intense pain @ site Rapid spread Gas may be evident on X-ray; crepitance is a late finding Overlying skin first pale then magenta/bronze Patient: o Fever may be mild/absent o Diaphoretic o Surprisingly alert/anxious o Tachycardic out of proportion to temperature For each degree C, heart rate increases by 10 bpm Death caused by: o Circulating red cell mass may decrease by half in a few hours (hypoxia of tissues in general)

o Hypotension, renal failure, metabolic acidosis, lack of

perfusion to cardiac muscle (arrhythmia) Clostridium probably wouldnt grow in blood, but would eat other tissues via blood and spread toxins Gas pockets are radioluscent on Xray Tuberculosis (Captain of all these men of death Sir William Ossler)

Caseous necrosis (cheese analogy gross / blue cheese in lung) Form of coagulative necrosis o Transient local ischemia Characteristic of infectious diseases that lead to granuloma response Granuloma formation host inflammatory cells (activated macs) form a circumscribed aggregate Cant see organisms on H&E (waxy cell wall), only activated macs/lymphocytes seen Cant kill organism macs can only wall off With time, some multinucleated giant cells formed by fusion of macrophages Center of granuloma undergoes caseous necrosis (low pO2 and low pH) o Central region will die o Outside intact/viable to protect host * Caseation first occurs with TB test + o May enlarge pink amorphous material Can eat away the organ consumption Acid fast for mycobacterium o Fat Necrosis: Lipase released from the pancreas attacked lipid in tissues (itself and surrounding) fatty acids then combine with calcium to form chalky areas (soaps) Pancreatic insult (acute pancreatitis alcoholics trauma) Microscopically: complete digestion in areas Dystrophic vs. Metastatic calcification o Dystrophic: occurs at site of injury if dead tissue not removed (fat necrosis) or a consequence of wear & tear Serum calcium WNL Initiated intracellularly by ppts in mitochondria and interaction of calcium with phosphate groups due to phospholipids damage o Metastatic (later-site): occurs in otherwise normal tissues as a consequence of hypercalcemia Serum calcium above normal o Calcium very dark purple/blue on H&E Intracellular accumulations o Abnormal metabolism

Fatty liver * can be reversible phenomenon Frequent in alcohol abuse, diabetics, toxins Macrovesicular steatosis VLDLs cant be formed as normal (normally triacylglycerols packaged with cholesterol, proteins into VLDL and sent to adipocytes) Oil Red O highlights

Microvesicular steatosis less frequent, life threatening conditions o Fat in much smaller droplets o Reye Syndrome ASA, viral infections association o Protein folding transport o Lack of an enzyme Glycogen storage diseases Clear, white spaces in H&E, magenta in PAS Diastase degrades glycogen o Two sections compared one treated, one not; stained with PAS o PAS + Mucus, polysaccharides, glycan in fungi, glycogen Lysosomal storage disease o Ingestion of indigestible material Iron Hemosiderin a breakdown product of hemoglobin o Brownish/yellow granules Melanin also brown Lipofuchsin also brown Wear and tear pigment Typical with aging o Prussian blue stains hemosiderin blue Lipofuchsin caused by autophagy as part of house keeping Brown/gold/yellow colored granules Prussian blue negative No great consequence to cell Electron dense granules on EM Both iron/Lipofuchsin in liver Prussian blue to distinguishing Lipid Ischemia vs. Hypoxia Ischemia cause hypoxia Not all hypoxia due to ischemia Hypoxia causes: anemia, CO poisoning, etc * -lymphocytes stain small & dark blue in H&E *